Abstract
Neurons polarize to form elaborate multiple dendrites and one long axon. The establishment and maintenance of axon/dendrite polarity are fundamentally important for neurons. Recent studies have demonstrated that the polarity complex PAR-3–PAR-6–atypical protein kinase C (aPKC) is involved in polarity determination in many tissues and cells. The function of the PAR-3–PAR-6–aPKC protein complex depends on its subcellular localization in polarized cells. PAR-3 accumulates at the tip of growing axons in cultured rat hippocampal neurons, but the molecular mechanism of this localization remains unknown. Here we identify a direct interaction between PAR-3 and KIF3A, a plus-end-directed microtubule motor protein, and show that aPKC can associate with KIF3A through its interaction with PAR-3. The expression of dominant-negative PAR-3 and KIF3A fragments that disrupt PAR-3–KIF3A binding inhibited the accumulation of PAR-3 and aPKC at the tip of the neurites and abolished neuronal polarity. These results suggest that PAR-3 is transported to the distal tip of the axon by KIF3A and that the proper localization of PAR-3 is required to establish neuronal polarity.
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References
Craig, A.M. & Banker, G. Neuronal polarity. Annu. Rev. Neurosci. 17, 267–310 (1994).
Dotti, C.G., Sullivan, C.A. & Banker, G.A. The establishment of polarity by hippocampal neurons in culture. J. Neurosci. 8, 1454–1468 (1988).
Bradke, F. & Dotti, C.G. Establishment of neuronal polarity: lessons from cultured hippocampal neurons. Curr. Opin. Neurobiol. 10, 574–581 (2000).
Fukata, Y., Kimura, T. & Kaibuchi, K. Axon specification in hippocampal neurons. Neurosci. Res. 43, 305–315 (2002).
Kemphues, K. PARsing embryonic polarity. Cell 101, 345–348 (2000).
Jan, Y.N. & Jan, L.Y. Asymmetric cell division in the Drosophila nervous system. Nature Rev. Neurosci. 2, 772–779 (2001).
Ohno, S. Intercellular junctions and cellular polarity: the PAR–aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol. 13, 641–648 (2001).
Shi, S.H., Jan, L.Y. & Jan, Y.N. Hippocampal neuronal polarity specified by spatially localized mPar-3–mPar-6 and PI 3-kinase activity. Cell 112, 63–75 (2003).
Lin, D. et al. A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000).
Kondo, S. et al. KIF3A is a new microtubule-based anterograde motor in the nerve axon. J. Cell Biol. 125, 1095–1107 (1994).
Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J. Cell Biol. 130, 1387–1399 (1995).
Yang, Z. & Goldstein, L.S. Characterization of the KIF3C neural kinesin-like motor from mouse. Mol. Biol. Cell 9, 249–261 (1998).
Muresan, V. et al. KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles. Mol. Biol. Cell 9, 637–652 (1998).
Goldstein, L.S. & Yang, Z. Microtubule-based transport systems in neurons: the roles of kinesins and dyneins. Annu. Rev. Neurosci. 23, 39–71 (2000).
Lupas, A., VanDyke, M. & Stock, J. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).
Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. Cloning and characterization of KAP3: a novel kinesin superfamily-associated protein of KIF3A/3B. Proc. Natl Acad. Sci. USA 93, 8443–8448 (1996).
Takeda, S. et al. Kinesin superfamily protein 3 (KIF3) motor transports fodrin-associating vesicles important for neurite building. J. Cell Biol. 148, 1255–1265 (2000).
Jimbo, T. et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nature Cell Biol. 4, 323–327 (2002).
Akimoto, K. et al. EGF or PDGF receptors activate atypical PKCλ through phosphatidylinositol 3-kinase. EMBO J. 15, 788–798 (1996).
Izumi, Y. et al. An atypical PKC directly associates and co-localizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).
Suzuki, A. et al. Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J. Cell Biol. 152, 1183–1196 (2001).
Inagaki, N. et al. CRMP-2 induces axons in cultured hippocampal neurons. Nature Neurosci. 4, 781–782 (2001).
Fukata, Y. et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature Cell Biol. 4, 583–591 (2002).
Acknowledgements
We thank M. Fukata, M. Nakagawa and J. Noritake for discussion; M. Yoshizaki and K. Fujii for preparing materials and technical assistance; T. Ishii for secretarial assistance. This research was supported by Grants-in-Aid for Scientific Research and Grant-in-Aid for Creative Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Organization for Pharmaceutical Safety and Research.
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Nishimura, T., Kato, K., Yamaguchi, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity. Nat Cell Biol 6, 328–334 (2004). https://doi.org/10.1038/ncb1118
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DOI: https://doi.org/10.1038/ncb1118
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